KCNH2 Variant G657I Detail

We estimate the penetrance of LQTS for KCNH2 G657I is 49%. We are unaware of any observations of this variant in individuals. G657I is not present in gnomAD. G657I has been functionally characterized in 1 papers. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G657I around 49% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 46
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT2 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 6 4 -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
17823114 Xeno -53.7 None None 0.718120805

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
17823114 Xeno None None None

G657I has 61 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: some residues appear multiple times at different distances since the functional KV11.1 channel (protein product of KCNH2/hERG) is a homotetramer and occasionally the same residue from multiple subunits is present within the 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
657 0 G657V, G657S,
658 4
660 5 S660L,
659 5
654 6
656 6 F656L, F656L, F656L,
661 6 A661V,
655 6
653 6
660 7 S660L,
653 8
662 8
664 8 Q664X,
652 9 Y652X,
553 9 L553V,
663 10
663 10
664 10 Q664X,
654 10
651 10 M651K,
661 10 A661V,
657 10 G657V, G657S,
657 10 G657V, G657S,
659 11
650 11 L650X,
550 11
650 11 L650X,
649 11
665 11 R665Q,
656 12 F656L, F656L, F656L,
554 12
549 12 V549M,
652 12 Y652X,
557 13
658 13
649 13
671 13 A671G, A671Del,
662 13
648 13 G648A,
658 13
667 13 Y667X,
652 13 Y652X,
660 13 S660L,
653 14
656 14 F656L, F656L, F656L,
655 14
651 14 M651K,
556 14
666 14
648 14 G648A,
552 14 L552S,
546 14
657 14 G657V, G657S,
661 14 A661V,
653 14
660 15 S660L,
623 15 T623I,
670 15
668 15 S668L,
666 15
622 15 L622F,